Ramucirumab plus paclitaxel as switch maintenance versus continuation of oxaliplatin-based chemotherapy in patients (pts) with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: The ARMANI phase III trial.

Background: In pts with HER2-negative advanced gastric/GEJ cancer and PD-L1 low/absent expression, platinum/fluoropyrimidine doublets are a standard first-line therapy. In this patient population, the outcomes are unsatisfactory and second-line therapy is given in only 40% of clinical trial patients. Switch consolidation maintenance may prolong the benefit of the initial strategy and delay clinical deterioration. Despite ramucirumab failing to prolong both progression-free survival (PFS) and overall survival (OS) in the first-line setting, paclitaxel plus ramucirumab is a standard second-line therapy and warrants investigation as a post-induction strategy. Methods: Pts with HER2-negative advanced gastric/GEJ cancer without disease progression after 3 months of initial oxaliplatin-based chemotherapy, stratified by site of origin (GEJ vs gastric), prior gastrectomy and peritoneal disease, were randomized 1:1 to ramucirumab 8 mg/Kg on days 1,15 plus paclitaxel 80 mg/sqm on days 1,8,15 every 28 days (arm A) vs CAPOX/FOLFOX at the same doses used in the last induction cycle, for additional 3 mos followed by fluoropyrimidine monotherapy maintenance (arm B). The primary endpoint was PFS, OS was a key secondary endpoint; quality of life, safety, and biomarkers were evaluated. A sample size of 280 pts achieved a 90% power to detect as significant at a 5% level (2-sided log-rank test) a median PFS increase from 4 to 6 mos (target HR=0.67). HRs were estimated by Cox models adjusting for stratification factors. Restricted Mean Survival Time (RMST) analysis was conducted in case of violation of proportional hazards assumption. Results: From Jan 2017 to Oct 2023, 280 patients were randomly assigned (144 arm A/136 arm B). Baseline characteristics were: male sex 67/61%, median age 64/66 years, PS 0 74/65%, GEJ 26/26%, prior gastrectomy 28/23%, peritoneal metastases 53/42%. At a median follow-up of 43.7 months (IQR 22.0-57.9), median PFS was 6.6 vs. 3.5 mos in Arm A vs. B (HR=0.63, 95%CI 0.49-0.81; P<0.001). 24-mos RMST analysis showed a statistically significant 2.4-mos average increment (p=0.002). Median OS was 12.6 vs. 10.4 mos in Arm A vs. B (HR=0.75, 95%CI 0.58-0.97; P=0.030). The frequency of grade >= 3 adverse events was 40.4% vs. 20.7% in arms A vs. B, respectively, mainly neutropenia 25.5/9.6%; febrile neutropenia 2.1/0%; hypertension 6.4/0%; venous thromboembolism 2.1/0%; peripheral neuropathy 5.7/6.7%. No treatment-related deaths were reported. Conclusions: Switch maintenance with paclitaxel plus ramucirumab after 3 months of oxaliplatin-based doublets may be a new strategy in patients with HER2-negative metastatic gastric/GEJ cancer who are non-eligible for initial immune checkpoint inhibitor-based regimens according to specific guidelines and regulatory approvals. Clinical trial information: NCT02934464.